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New Sequential Reactions with Single-Electron-Donating Agents.

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New Sequential Reactions with Single-Electron-Donating Agents
Troels Skrydstrup*
The construction of complex organic compounds by sequential transformations is one of the most impressive and efficient
synthetic strategies, which clearly demonstrates the imagination
and creativity of synthetic chemists. The advantages of the use
of such tandem reactions are many and have been thoroughly
discussed by Tietze and Beifuss in a review in 1993."' Now
through the work of the groups of Molander and Murphy three
newly discovered sequential reactions may be added to this
growing list of transformations relying on single electron-donating agents such as samarium diiodide and tetrathiofulvalene.
These new sequential reactions provide an effective and elegant
means to a series of polycyclic compounds.
Of the plethora of contemporary reagents at our disposal for
organic synthesis, perhaps the most remarkable is the divalent
lanthanide reagent samarium diiodide.[" This unique, polyvalent reducing agent has been applied to a multitude of important synthetic transformations, which generally proceed with
high levels of stereochemical control. The secret to the success of
this one-electron-donating agent lies in its intermediate reducing
potential: cither a radical o r a carbanionic reaction may be
efficiently performed through the judicious choice of reactants
and conditions. As has been demonstrated by several groups,
these two reaction types may furthermore be combined in a
tandem process known as a radical/polar sequence.[31Specifically, an initial Sm1,-induced radical cyclization may be succeeded
by a second electron transfer from a second equivalent of SmI,,
affording the corresponding organosamarium intermediate
with concomitant intermolecular nucleophilic addition or sub~titution.~
cyclizations are thereby terminated by the
introduction of rather than the loss of functional groups, as is
characteristic for cyclizations with tin hydride.
In an extension of this chemistry Molander and Harris have
recently demonstrated that SmI, may be employed in either an
anionic/anionic or an anionic/radical sequential reaction for the
stereocontrolled construction of complex bicyclic and tricyclic
ring systems, which enhances even further the versatility and
possibilities of this reagent.[4, 51 The Molander team, who greatly contributed to the popularity of this reagent over the last
decade, had previously observed that nucleophilic acyl substitu[*] Dr T Skrydstrup
UniversitP Parts-Sud, Laboratoire de Synthese de BiomolCcules
lJRA CNRS 462, Institut de Chimie Moleculaire
F-91405 Orsny Ckdex (France)
Fax: Int. codc + ( I ) 6985-3715
e-mail skryda!ir
Scheme 1. SmI,-induced iiuclcophilic acyi substitutioii
tion reactions proceed exceptionally well to afford cyclic or
acyclic ketones (Scheme 1).[61 Considering that SmI, promotes
Barbier-type cyclization reactions with alkyl halides, it seemed
possible to combine these two transformations in a sequential
manner. This was exactly the case: when the simple-to-prepare
substrates shown in Scheme 2 were subjected to four equivalents
of SmI, rather than the usual two equivalents, a diverse array of
cyclic products formed depending on the substitution pattern of
In the mechanism proposed for these reactions
a tetrahedral intermediate is formed upon nucleophilic addition
of an organosamarium species, which is generated upon SmI,
addition. Liberation of the ketone is then followed by a second
intramolecular attack upon reduction of the sccond alkyl halide
side chain. Crucial to the success of some of these reactions is the
sequential formation of the organosamarium intermediates,
which is controlled by the different rates at which alkyl halides
are reduced by Sml, (/<,,d(R-l) > /c,,~(~-,-,J. When the same
halide is employed in the two side chains, it is apparently their
length that determines the sequence or attack to the carbonyl
functionality. A wide variety of ring systems are accessible by
this approach, including seven- and eight-membered rings.
Highly iinpressive are the efficient transformations sketched in
the last two examples in Scheme 2. The rcsulting tricyclic systems are related to certain naturally occurring sesqui- and sesterterpenes.
Molander and Harris also demonstrated the efficiency of the
Sm1,-promoted anioniciradical sequence as a viable approach
to similar ring systems.[51Basically the same starting materials
are exploited again, with one minor but important modification: one of the alkyl halide side chains has been replaced with
a side chain containing a double bond. The logic behind these
examples is that in the absence of a second alkyl halide reduction step, the intermediate ketone formed after acyl substitution
is reduced to the ketyl radical, which attacks the olefin with ring
formation. As shown by the examples in Scheme 3, this ap-
First anionic
Second anionic
Ketyl radical
Sm12, Ht
uoH -
4 SmI2
SmI, (4equiv)
4 Sm12
Sm12 (4 equiv)
Scheme 2. Several examples of anionic/anionic sequential reactions promoted
by SmI,. HMPA = hexamethylphosphoric trlamide, TBS = m-butyldimethyls1lyl.
proach also provides a n efficient and facile route to numerous
substituted carbo- and heterocycles,['"] and in general proceeds
with high diastereoselectivity. This bicyclization process gives
the best yields when the substrates bear activating groups on the
A nice extension of this chemistry to a sequential anionic/radical/anionic sequence was also d e ~ c r i b e d .Normally
after acyl
addition and radical cyclization onto a C=C bond, the newly
formed carbon radical is reduced to an organosamarium intermediate, which is subsequently protonated. However, this
organosamarium species may be trapped in the presence of a
ketone, thus terminating this three-step process (Scheme 4). Until now only a single representative has been reported, but this
example certainly suggests the possibility of extending these
Sm1,-induced sequential reactions even further.
Another impressive array of radical/polar sequential reactions employs an alternative one-electron-donating agent previously not been exploited in organic synthesis, namely tetrathiafulvalene (TTF). In contrast to the traditional radical/polar
reactions induced by SmI, ,I3] Murphy and collaborators have
demonstrated that radical cyclizations promoted by TTF may
be terminated by S,l -type nucleophilic substitution at the new
mhH. D-69451 Weinhelm, 1997
(6 : 1)
Scheme 3. Several examples of anionic/radical sequential reactions promoted by
SmI,. TMS = trimethylsilyl
Scheme 4. An example of a anlonic/radical/dnionic sequential reaction promoted
by SmI,.
exocyclic center (Scheme 5 ) .['I After single-electron reduction of
a suitable substrate A by TTF and subsequent radical cyclization in analogy to the Sm12-promoted reactions, the newly
formed carbon radical is formally oxidized by combination with
the TTF.+ radical cation. The carbon radical is not reduced
further by a second TTF molecule, as is the case in Sm1,-medi-
0870-083319713604-0346S 18.00+ .28/0
Angeu Chem. Int. Ed. Engl. 1997, 36, No. 4
' \ . - - . L R
radical cyclization
Scheme 5. Comparison of Sm1,- and TTF-induced radical/polar sequential reactions.
1) NOBF4
2 ) TTF
C (R=S02Me)
R = SOZPh, 68%
R = SO,Me, 75%
R f i
Scheme 6. Degradation of the ABCE tetracyclic substructure of aspidospermidine.
ated reactions, rather the corresponding sulfonium ion forms.
Substitution at the sulfonium ion bearing a carbon center with
external nucleophiles (for example solvents such as H,O,
MeOH, and CH,CN) were found to follow SJ-type kinetics.
These reactions have so far been applied only to aryl diazonium
salts and are hence restricted to cyclizations of aryl radicals. An
intriguing facet of this chemistry is that this radical/polar sequence can be carried out in the presence of a catalytic amount
of TTF, because the one-electron-donating agent is regenerated
after nucleophilic attack. This reaction is thus clearly distinguished from the samarium(r1)-induced reactions, in which two
equivalents of the reagent are necessary for the radical/anionic
Angew. Chem. Inl. Ed. Engl. 1991, 36, N o . 4
process. Further studies along this line are necessary, since the
best yields as well as acceptable reaction times were obtained
when one equivalent of TTF was employed.
In a more interesting application of this chemistry, substrates
containing internal nucleophiles can be used to construct more
complex ring systems.['] A cunning demonstration of this approach was provided by the Murphy group in their model studies for the preparation of the ABCE tetracyclic substructure of
the Aspidosperma alkaloids aspidospermidine and strychnine.[']
Diazotization of precursors B and C and their subsequent reaction with TTF were performed in situ to furnish the desired
tetracyclic ring systems in good yields (Scheme 6). Most importantly, the three contiguous stercocenters were formed with
complete stereocontrol, affording the all-cis product and
providing further evidence for the S,1 reaction with the sulfonium ion intermediate. This radical/polar sequential reaction
therefore complements nicely the tandem radical cyclization approach reported by the same group." O1 These new ring-forming
methodologies should prove to be a powerful means for the
efficient synthesis of complex natural products.
German version: Angew. Chem. 1997, i09, 355-358
Keywords: domino reactions * lanthanides polycycles radical
[I] L. F. Tietze, U. Beifuss, Angew. Chem. 1993, i05,137; Angew. Chem. Int. Ed.
Engl. 1993, 32, 131.
[2] For reviews, see a) G. A. Molander, C. R. Harris, Chem. Rev. 1996,96, 307; h)
G. A. Molander in Organic Reactions, Vol. 46 (Ed.: L. A. Paquette), Wiley,
New York, 1994, p. 211; c) Chem. Rev. 1992, 92, 29; d) D. P. Curran, T. L.
Fevig, C. P. Jaspersen, M. L. Totleben, Synlert 1992,943;e) H. B. Kagan, J. L.
Namy, Tetrahedron 1986, 42, 6573.
[3] For applications of these sequential reactions, see a) G. A. Molander, L. S.
Harring, J. Org. Chem. 1990,55,6171; b) D. P. Curran, T. L. Fevig, M. L. Totleben, Synlett 1990, 773; c) D. P. Curran, M. L. Totleben, J. A m . Chem. Soc.
1992,1i4,6050; d) M. L. Totlehen, D. P. Curran, P. Wipf, J Org. Chem. 1992,
57, 1740; e) G. A. Molander, J. A. McKie, ibid. 1992,57. 3132; f) ibid. 1995,60,
872; g) G. A. Molander, C. Kenny, ;bid 1991, 56, 1439; h) E. J. Enholm, A.
Trivellas, Tetrahedron L e n 1994, 35, 1627.
[4] G. A. Molander, C. R. Harris, J. Am. Chem. Suc. 1995, if 7, 3705.
[5] G. A. Molander, C. R. Harris, J. Am. Chem. Soc. 1996, fi8. 4059.
[6] a) G. A. Molander, J. A. McKie, J. Org. ('hem. 1993,58.7216;b) G. A. Molander, S. R. Shakya, ibid. 1994, 59, 3445.
[7] a) C. Lampard, J. A. Murphy, N. Lewis, J. Chem. SOC.Chem. Cummun. 1993,
295; b) R. J. Fletcher, C. Lampard. J. A. Murphy, N . Lewis, J. Chem. Soc.
Perkin Trans. i 1995, 623.
[XI J. A. Murphy, F. Rasheed, S. J. Roome, N. Lewis, Chem. Commun. 1996, 737.
[9] R. J. Fletcher, D. E. Hibbs, M. Hursthouse, C. Lampard, J. A. Murphy, S. J.
Roome, Chem. Commun. 1996, 739.
[lo] M. Kizil, J. A. Murphy, J. Chem. Soc. Chem. Cummun. 1995,1409; U. Koert,
Angew. Chem. 1996, 108,441 ; Angew. Chem. In!. Ed. Engl. 1996,35,405.
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